WO1991014676A1

WO1991014676A1 - New leucotriene b4 derivatives, methods of preparing them and their use as drugs

Info

Publication number: WO1991014676A1
Application number: PCT/DE1991/000249
Authority: WO
Inventors: Josef Heindl; Werner Skuballa; Bernd Buchmann; Wolfgang Fröhlich; Roland Ekerdt; Claudia Giesen
Original assignee: Schering Aktiengesellschaft Berlin Und Bergkamen
Priority date: 1990-03-19
Filing date: 1991-03-19
Publication date: 1991-10-03
Also published as: JPH05500227A; AU7498791A; HU914049D0; EP0801061A3; HUT60457A; CA2057042A1; EP0801061A2; US5614634A; US5440044A; EP0477311A1; FI915435A0; DE4009117A1

Abstract

The invention concerns leucotriene B4 analogues of formula (I), in which R1 is the residue COOR2, R2 being a hydrogen atom or a (C¿1?-C4)-alkyl group, or R?1¿ is the residue CH¿2?OH, B is an alkylene group with 1 to 3 C-atoms in the chain, a residue (a) or a residue (b) in which R?3¿ is a hydrogen atom, a carboxyl group or a methoxycarbonyl group, A is the (c), -O-, (d), -NH-CO-, -CO-NH-, -OCH¿2?-, -CH=CH-, (e), -COCH2- or -CHOH-CH2-group, X is N or CH, D is a (f) or (g) group and (h) is a single or double bond, as well as, optionally, the salts of these compounds with physiologically safe bases, methods of preparing them and their use in pharmaceutical preparations.

Description

New leukotriene B ₄ derivatives, process for their preparation

and their use as medicines

The invention relates to new leukotriene B ₄ derivatives, processes for their preparation and their use as medicaments.

Leukotriene B ₄ (LTB ₄ ) was discovered in 1979 by B. Samuelsson and co-workers as a metabolite of arachidonic acid. In biosynthesis, the enzyme 5-lipoxygenase initially forms the leukotriene A ₄ as a central intermediate, which is then converted into the LTB ₄ by a specific hydrolase. Lipoxygenase

L

The nomenclature of leukotrienes can be found in the following work: a) B. Samuelsson et. al., Prostaglandins 19, 645 (1980); 17, 785 (1979). b) CN Serhan et al., Prostaglandins 34, 201 (1987).

The physiological and especially the pathophysiological significance of leukotriene B ₄ is summarized in some recent work: a) The Leukotrienes, Chemxstry and Biology eds. LW Chakrin, DM Bailey, Academic Press 1984. b) JW Gillard et al., Drugs of the Future 12, 453 (1987). c) B. Samuelsson et al., Science 237, 1171 (1987). d) CW

Parker, Drug Development Research 10, 277 (1987). It follows that LTB _{4 is} an important inflammation mediator for inflammatory diseases in which leukocytes migrate into the diseased tissue.

The LTB ₄ is known to cause leukocyte adhesion to the blood vessel wall. LTB ₄ is chemotactically active, ie it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration. It also indirectly changes vascular permeability due to its chemotactic activity, a synergism with prostaglandin E _{2 has been} observed. LTB ₄ obviously plays a crucial role in inflammatory, allergic and immunological processes.

Leukotrienes and especially LTB ₄ are involved in skin diseases that are associated with inflammatory processes (increased vascular permeability and edema, cell infiltration), increased proliferation of skin cells and itching, such as eczema, erythema, psoriasis, pruritus and acne. Pathologically elevated leukotriene concentrations are either causally involved in the development of many dermatitis, or there is a connection between the persistence of the dermatitis and the leukotrienes. Significantly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis or atopic dermatitis.

Furthermore, leukotrienes and LTB _{4 are} particularly useful for arthritis, chronic lung disease (e.g. asthma), rhinitis and inflammatory bowel diseases.

Antagonists against LTB ₄ itself or inhibitors of those enzymes involved in the

Synthesis of the LTB ₄ involved can be effective as specific remedies, especially against diseases that are associated with inflammation and allergic reactions.

In addition to therapeutic options that can be derived from an antagonization of LTB ₄ with LTB ₄ analogs, the

Usefulness and potential use of leukotriene B ₄ agonists for

Treatment of fungal skin diseases (H. Katayama,

Prostaglandins 34, 797 (1988)).

Further applications for LTB ₄ agonists result from the

LTB ₄ -stimulated activation of components of the immune system for various indications, such as infectious diseases, burn injuries, in tumor therapy or, for example, in AIDS therapy. For example, a reduced release of LTB ₄ when stimulating neutrophils has been reported in AIDS patients. (AIDS, 1989, 3, 651).

The invention relates to new leukotriene B ₄ analogs of the formula I,

wherein

R ^{1 represents} the radical COOR ² with R ² meaning a hydrogen atom or a

(C ₁ -C ₄ ) alkyl group or R ^{1 is} CH ₂ OH,

β an alkylene group with 1-3 carbon atoms in the chain, a remainder or a radical with R ₃ in the meaning of a

Hydrogen atom, a carboxy or alkoxycarbonyl group with 1-4 C atoms in the alkoxy radical,

A the groups, -O-, - -, -NH-CO-, -CO-NH-, -OCH -, -CH = CH-, -C≡C-,

-COCH ₂ -,

OH

or -CHOH-CH ₂ -

X N or CH,

D the groups or and

..... mean a single or double bond, and optionally their salts with physiologically acceptable bases.

Suitable alkyl groups R ₂ are straight-chain or branched-chain alkyl groups with 1-4 C atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.

Preferred alkyl groups R ₂ are those with 1-2 carbon atoms.

Suitable alkylene groups B are straight-chain or branched-chain, saturated alkylene radicals with 1-3 C atoms. Examples include: the methylene, the ethylene, the 1,2-propylene and in particular the trimethylene group. Inorganic and organic bases are suitable for salt formation, as are known to the person skilled in the art for the formation of physiologically compatible salts. Examples include alkali metal hydroxides such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.

The leukotriene B ₄ derivatives of the formula I form with α-, β-, γ-cyclodextrin

Cyclodextrin clathrates.

Particularly preferred compounds of the present invention are compounds of the formula I in which

R ¹ COOH, COOCH ₃ or COOC ₂ H ₅ ,

B - (CH ₂ ) _n with n = 1 -3,

A the groups, -O- -NH-CO-, -CO-NH-, -OCH ₂ -, -CH = CH-, -C≡C-,

-COCH ₂ -,

O

or -CHOH-CH ₂ -,

X N or CH,

D the groups or and

...... represents a single bond.

The invention also relates to a process for the preparation of the leukotriene B ₄ derivatives of the formula I according to the invention, which is characterized in that in a manner known per se

a) a compound of formula II

wherein D has the meaning given above and .... an Emfach or

Double bond and X represent nitrogen and where Z symbolizes a bromine atom or an iodine atom, after reaction with n-butyllithium with a compound of formula III

R ¹ -BR ⁴ (III), wherein R ¹ and B have the meanings given above and R ⁴ the radicals

-CHO or -COOCH ₃ means, converts, or

b) a compound of the formula IV,

(IV),

wherein R ¹ , B, A and Z have the meanings given above and X

Means nitrogen with a tri-n-butylstannane of the formula V,

wherein ..... represents a single or a double bond in the presence of a palladium catalyst, such as, for example, 1,1'-bis (diphenylphosphino) ferrocene-palladium-II-chloride,

or

c) a phenylene derivative of the formula VI,

where D is the groups

or Ac is an acyl group with bis

to 8 carbon atoms and ... mean a single or a double bond, with a Grignard compound of the general formula VII,

in which B has the abovementioned meaning, Y represents a chlorine atom or a bromine atom and the substituents R ₅ , R ₆ and R _{7 are} identical or different and are C ₁ -C ₄ alkyl groups or phenyl groups, the free hydroxyl group is acylated, the silyl ether is split off and, if desired, the hydroxymethyl compound is oxidized to the carboxyl compound, and any acyl groups are split off and the carboxyl group is esterified or converted into its salts.

The starting compounds II, IV and VI are prepared in accordance with the processes given in the examples.

The reaction of the compounds of formula II with compounds of

Formula III is carried out in a manner known per se as indicated in the relevant examples. As far as the solvent, temperature and reaction time are concerned, the reaction conditions specified therein are of course not only limited to the information in the examples, but can be modified within a range that can be understood by the person skilled in the art. The same applies to the implementation of IV with V or VI with VII.

The tert-butyl-dimethylsilyl group or the tert-butyldiphenylsilyl group is preferably used as the silyl ether protective group of the Grignard reagent of the formula VII.

The hydroxyl groups are oxidized by methods known to those skilled in the art. The following can be used as oxidizing agents: pyridinium dichromate (Tetrahedron Letters, 1979, 399), Jones reagent (J. Chem. Soc. 1953, 2555) or platinum / oxygen (Adv. In Carbohydrate Chem. 17, 169 (1962) or Collins- Oxidation and subsequent Jones oxidation. The oxidation with pyridinium chromate is carried out at temperatures from 0 ° C. to 100 ° C., preferably 20 ° C. to 40 ° C., in a solvent which is inert to the oxidizing agent, for example dimethylformamide.

The oxidation with Jones reagent is carried out at temperatures from -40 ° C to + 40 ° C, preferably -30 ° C to 0 ° C in acetone as a solvent.

The oxidation with platinum / oxygen is carried out at temperatures of 0 ° C to 60 ° C, preferably 20 ° C to 40 ° C in an inert solvent against the oxidizing agent, such as. B. ethyl acetate.

The saponification of the esters of the formula I is carried out by the methods known to the person skilled in the art, for example using basic catalysts. The compounds of the formula I can be separated into the optical isomers by the customary separation methods.

The release of the functional. modified hydroxy groups is carried out according to known methods. For example, the removal of hydroxy protecting groups in an aqueous solution of an organic acid, such as e.g.

Oxalic acid, acetic acid, propionic acid, etc., or in an aqueous solution of an inorganic acid, such as. B. hydrochloric acid. To improve the solubility, a water-miscible inert organic solvent is advantageously added. Suitable organic solvents are e.g. B. alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferred. The cleavage is preferably carried out at temperatures between 20 ° C and 80 ° C. The silyl ether protective groups are cleaved off, for example, with tetrabutylammonium fluoride or with potassium fluoride in the presence of a crown ether. Suitable solvents are, for example, tetrahydrofuran, diethyl ether, dioxane, methylene chloride, etc. The cleavage is preferably carried out at temperatures between 0 ° C. and 80 ° C. The saponification of the acyl groups takes place, for example, with alkali or alkaline earth carbonates or hydroxides in an alcohol or in the aqueous solution of an alcohol. Aliphatic alcohols, such as, for example, methanol, ethanol, butanol, etc., are preferably suitable as alcohol

Methanol. Potassium and sodium salts may be mentioned as alkali carbonates and hydroxides. The potassium salts are preferred.

Calcium carbonate, calcium hydroxide and barium carbonate are, for example, suitable as alkaline earth carbonates and hydroxides. The reaction takes place at -10 ° C to + 70 ° C, preferably at + 25 ° C.

The leukotriene B ₄ derivatives of formula I with R ₂ in the meaning of a

Hydrogen atoms can be converted into a salt with suitable amounts of the corresponding inorganic bases with neutralization. For example, when the corresponding acids are dissolved in water containing the stoichiometric amount of the base, the water is evaporated or a water-miscible solvent, e.g. Alcohol or acetone, the solid inorganic salt.

To produce an amine salt, the LTB ₄ acid is dissolved, for example, in a suitable solvent, for example ethanol, acetone, diethyl ether, acetonitrile or benzene, and at least the stoichiometric amount of the amine is added to this solution. The salt is usually obtained in solid form or is isolated in a conventional manner after evaporation of the solvent.

If the starting product contains OH groups in the leukotriene B ₄ residue, these OH groups are also reacted. If end products which contain free hydroxyl groups are ultimately desired, it is expedient to start with starting products in which these are temporarily protected by ether or acyl residues, which are preferably readily removable. The replacement of the chemically and metabolically unstable cis-Δ ^6.7 double bond and the trans-Δ ^8.9 double bond of the LTB ₄ by a 1,3-substituted one

Phenyl or 2,6-substituted pyridyl ring leads to more stable

Leukotrienes with a phenyl or pyridyl ring in the 6,9 position. Depending on the meaning of the individual radicals R, A, D and the derivatization of the functional groups, the compounds of the general formula I are either

a) chemically stable LTB ₄ agonists or

b) chemically stable LTB ₄ antagonists.

With the compounds of formula I, which are receptor agonists, the LTB ₄ receptor mediated stimulated activation of components of the

Immune system for various indications, such as infectious diseases,

Mycoses, burn injuries, in tumor therapy or e.g. in the

AIDS therapy can be used therapeutically. For example, a reduced release of LTB ₄ when stimulating neutrophils has been reported in AIDS patients.

The compounds of formula I, which are receptor antagonists, have anti-inflammatory and anti-allergic effects. Hence the new ones

Leukotriene B ₄ derivatives of the formula I are valuable active pharmaceutical ingredients. The compounds of the formula I are particularly suitable for topical application, since they have a dissociation between the desired topical activity and undesirable systemic side effects.

These new leukotriene B ₄ derivatives of the formula I are suitable in

Combination with the auxiliaries and carriers customary in galenical pharmacy for the local treatment of contact dermatitis, various types of eczema, neurodermatoses, erythroderma, pruritis vulvae et ani, rosacea, erythematosus cutaneus, psoriasis, lying ruber planus et verrueosus and similar skin diseases. The new leukotriene B ₄ derivatives are also suitable in the form of capsules,

Tablets or coated tablets, which preferably contain 0.1 to 100 mg of active ingredient or are administered orally or in the form of suspensions, which preferably contain 1-200 mg of active ingredient per dose unit and are applied rectally, also for the treatment of allergic diseases of the intestinal tract, such as ulcerative colitis and granulomatous colitis.

In addition, the new compounds, if appropriate in combination with the customary carriers and auxiliaries, are also well suited for the production of inhalants which can be used for the therapy of allergic diseases of the respiratory tract such as bronchial asthma or rhinitis.

The new leukotriene B ₄ derivatives, which are LTB ₄ antagonists, can also be used in combination, for example with lipoxygenase inhibitors, cyclooxygenase inhibitors, prostacyclin agonists, thromboxane antagonists, leukotriene

D ₄ antagonists, leukotriene E ₄ antagonists, leukotriene F ₄ antagonists,

Phosphodiesterase inhibitors or PAF antagonists can be used.

The pharmaceutical specialties are produced in the usual way by converting the active ingredients with suitable additives into the desired application form, such as: solutions, lotions, ointments, creams or plasters. In the medicinal products so formulated, the active substance concentration depends on the form of application. For lotions and ointments, an active ingredient concentration of 0.0001% to 1% is preferably used.

The following exemplary embodiments serve to explain the method according to the invention. EXAMPLE 1

(5RS) -5-Hydroxy-5- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyl} pentanoic acid methyl ester

A. A solution of 516 mg of 2,6-dibromopyridine in 4 ml of dimethylformamide is mixed with 1 g of (1E) -1- (tri-n-butylstannyl) -1-undecen- (3RS) -3-ol and 81 mg

1,1'-bis- (diphenylphosphino) -ferrocene-palladium-I I - chloride are added and the mixture is stirred under an atmosphere for 24 hours at room temperature. The reaction mixture is poured into 20 ml of 5% hydrochloric acid

Shaken out diethyl ether, the organic phase dried with sodium sulfate and concentrated. The residue is on silica gel

Chromatographed hexane / ethyl acetate / triethylamine 95/5/1. This gives 355 mg of 2-bromo-6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine as a colorless oil.

IR (CHCl ₃ ): 2925, 2860, 1655, 1575, 1548, 1432, 1120, 985 cm ^-1 .

The organotin compound used in Example 1A is described in German patent application P 3909326.3.

B. A solution of 326 mg of 2-bromo-6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine in 5 ml of tetrahydrofuran is stirred at -78 ° C in an argon atmosphere with 1.25 ml of n-butyllithium (1.6 molar in hexane) was added. After 10 minutes, a solution of 5-0xo-pentanoic acid methyl ester in

1 ml of tetrahydrofuran added at -78 ° C and stirred for 2 hours at this temperature. The reaction mixture is mixed with water, extracted with dichloromethane, dried over sodium sulfate, concentrated and the crude product is chromatographed on silica gel with hexane / ethyl acetate 98/2. This gives 188 mg of the title compound as a colorless oil.

IR (CHCl ₃ ): 3600, 2925, 2860, 1730, 1574, 1455, 1260, 1010 cm ^-1 . EXAMPLE 2

(5RS) -5-Hydroxy-5- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyl} pentanoic acid

A solution of 140 mg (5RS) -5-hydroxy-5- {6 - {(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyl} pentanoic acid methyl ester in 6 ml of methanol is mixed with 6 ml 0.5 N sodium hydroxide solution was added and the mixture was stirred at room temperature for 2 hours. The methanol is removed in vacuo, the residue is acidified to pH 4 with 0.5N sulfuric acid, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated. This gives 125 mg of the title compound as a colorless oil.

IR: 3370, 2960, 2922, 2852, 1710, 1570, 1455, 1260, 1080, 1020, 800 cm ^-1 .

EXAMPLE 3

2 - [(1RS) -1-Hydroxy-1- (3-methoxycarbonylphenyl) methyn-6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine

Under the conditions of Example 1B, 326 mg of 2-bromo-6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine are mixed with 1.38 ml of n-butyllithium (1.6 molar in hexane) and 181 mg of 3-formylbenzoic acid methyl ester (J. Org. Chem. 31, 1966, 2585), processed and chromatographed on silica gel with hexane / ethyl acetate 8/2. 105 mg of the title compound are obtained as a colorless oil.

IR: 2030, 2860, 1720, 1290. 1095 cm ^-1 .

EXAMPLE 4

2 - [(1RS) -1-Hydroxy-1- (3-carboxyphenyl) methyl] -6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine

Under the conditions of Example 2, 80 mg of 2 - [(1RS) -1-hydroxy- 1- (3-methoxycarbonylphenyl) methyl] -6- [ME) - (3RS) -3-hydroxy-1-undecenyl] - saponified and prepared pyridine in 4 ml of methanol with 4 ml of 0.5N sodium hydroxide solution. There are 40 mg of the title compound as a colorless foam hold .

IR: 3400, 2925, 2855, 1695, 1570 ', 1455, 1262, 970, 750 cm ^-1 .

EXAMPLE 5

3- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyloxy} benzoic acid methyl ester

A. A solution of 2.37 g of 2, 6-di-bromopyridine and 1.52 g of methyl 3-hydroxybenzoate in 10 ml of dimethylformamide is mixed with 6.6 g of cesium carbonate and heated at 120 ° C. for 3 hours with stirring. The reaction mixture is filtered through kieselguhr, washed with dichloromethane and the filtrate is concentrated in vacuo. The residue is distilled at 140-150 ° C and 0.04 barn on a Kugelrohr. There are 2.98 g

Methyl 3- (6-bromo-2-pyridyloxy) benzoate, melting point

Get 68-69 ° C.

IR (CHCl ₃ ): 2925, 1720, 1580, 1560, 1420, 1285. 1100 cm ^-1 .

B. A solution of 617 mg of 3- (6-bromo-2-pyridyloxy) -benzoic acid methyl ester in 4 ml of dimethylformamide is mixed with 1.09 g (1 U) -1- (tri-n-butylstannyl) - 1-undecen- ( 3RS) -3-ol and 74 mg of 1,1'-bis- (diphenylphosphino) -ferrocene-palladium-II-chloride were added and the mixture was stirred under an argon atmosphere at room temperature for 48 hours. The reaction mixture is chromatographed on silica gel with hexane / ethyl acetate = 9/1. 340 mg of crude product are obtained as a yellow oil, which is subjected to methanol / water = 9/1 for complete purification of the high pressure liquid chromatography on silanized silica gel (RP 18 material). 160 mg of the title compound are thus obtained as a colorless oil.

IR (CHCl ₃ ): 3605, 2930, 1722, 1590, 1570, 1435, 1260, 1100, 1015 cm ^-1 .

EXAMPLE 6

3- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyloxy} benzoic acid

Under the conditions of Example 2, 40 mg of methyl 3- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyloxy} benzoate in 1 ml of metha saponified and prepared with 1 ml of 1N sodium hydroxide solution. 29 mg of the title compound of melting point 85-87 ° C. are obtained.

IR (CHCl ₃ ): 2930.1710, 1590, 1570, 1434, 1260, 1095, 1012 cm ^-1 .

EXAMPLE 7

4- {6 - [(1E) - (3RS) -3-Hydroxy-1-undecenyl] -2-pyridylcarbonylamino} -butyric acid ethyl ester

A. 4 g of 6-bromopyridine-2-carboxylic acid and 25 g of thionyl chloride are 1

Heated under reflux for one hour. The excess thionyl chloride is removed in vacuo and the residue is distilled in a bulb tube at 110 ° C. and 0.04 mbar. The 6-bromopyridine-2-carboxylic acid chloride thus obtained is dissolved together with 3.32 g of ethyl 4-aminobutyrate, hydrochloride in 40 ml of dioxane, mixed with 6 g of triethylamine while cooling with ice and stirred for 5 hours at room temperature. The reaction mixture is poured into water, extracted with diethyl ether, dried (sodium sulfate) and concentrated. The residue is distilled in a bulb tube at 170 ° C. and 0.04 mbar, and ma n receives 3.2 g of 4-ethyl (6-bromo-2-pyndylca rbonylamino) butyrate as a light yellow oil.

IR (CHCl ₃ ): 3400, 2930, 1720, 1675, 1520, 1425, 1300 cm ^-1 .

B. Under the conditions of Example 5B, 630 mg of 4- (6-bromo-2-pyridylcarbonylamino) butyric acid ethyl ester and 1.007 g of (1E) -1- (tri-n-butylstannyl) -1-undecen- (3RS) -3 -ol in 4 ml of dimethylformamide in the presence of 71 mg of 1,1'-bis- (diphenylphosphino) -ferrocene-palladium-II-chloride as a catalyst and the reaction mixture was chromatographed on silica gel with hexane / ethyl acetate = 95/5 to 8/2 . 300 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 3390, 2925, 2860, 1725, 1670, 1525, 1450, 1260 cm ^-1 . EXAMPLE 8

4- {6 - [(1E) - (3RS) -3-Hydroxy-1-undecenyl] -2-pyridylcarbonylamino} butyric acid

Under the conditions of Example 2, 60 mg of 4- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridylcarbonylamino} butyric acid ethyl ester in 1.5 ml of methanol are mixed with 1.5 ml of 1 n Saponified and processed sodium hydroxide solution. 35 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 3390, 2925, 2860, 1722, 1670, 1525, 1450, 1260 cm ^-1 .

EXAMPLE 9

5- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridylamino} -5-oxo-pentanoic acid methyl ester

A solution of 1.0 g of 2-amino-6-bromopyridine and 580 mg of triethylamine in 12 ml of tetrahydrofuran is added dropwise with stirring and ice cooling with 0.78 ml of methyl glutarate and the mixture is stirred for 17 hours at room temperature. The reaction mixture is poured into water, extracted with diethyl ether, the organic phase dried (sodium sulfate) and concentrated. The residue is chromatographed on silica gel with dichloromethane / methanol = 95/5. 668 mg of 5- (6-bromo-2-pyridylamino) -5-oxo-pentanoic acid methyl ester of melting point 128-131 ° C. are obtained.

B. Under the conditions of Example 5B, 603 mg of methyl 5- (6-bromo-2-pyridylamino) -5-oxopentanoate and 1.01 g of (1E) -1- (tri-n-butylstannyl) -1-undecene - (3RS) -3-ol in 12 ml of dimethylformamide in the presence of 71 mg of 1,1'-bis (diphenylphosphino) ferrocene-palladium-II-chloride as a catalyst and the reaction mixture on silica gel with hexane / ethyl acetate = 95 / 5 to 75/25 chromatographed. It 155 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 3420, 2925, 2860, 1730, 1695, 1575, 1450, 1260, 1095, 1010 cm ^-1 .

EXAMPLE 10

4- {6 - [(1E) - (3RS) -3-Hydroxy-1-undecenyl] -2-pyridylamino} -5-oxo-pentanoic acid

Under the conditions of Example 2, 60 mg of 4- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridylamino} -5-oxo-pentanoic acid methyl ester in 1.5 ml of methanol are mixed with 1 , 5 ml of 1 N sodium hydroxide solution and prepared. 40 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 2935, 2865, 1700, 1580, 1458 cm ^-1 .

EXAMPLE 11

4- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyloxy} acetic acid methyl ester

A. A suspension of 178 mg sodium hydride (80% dispersion in

Mineral oil) in 4 ml of dimethylformamide under argon atmosphere, stirring and ice cooling with a solution of 361 mg of glycolic acid methyl ester in

2 ml of dimethylformamide are added and the mixture is stirred at room temperature for 3 hours. A solution of 948 mg of 2,6-dibromopyridine in 2 ml of dimethylformamide is then added with ice-cooling and the mixture is stirred at room temperature for 48 hours. The reaction mixture is poured onto ice and extracted with ethyl acetate. The organic phase is washed 4 times with saturated sodium chloride solution, dried over sodium sulfate and concentrated. 790 mg of 2- (6-bromo-2-pyridyloxy) methyl acetate are obtained as an oily crude product.

B. Under the conditions of Example 5B, 780 mg of the above crude product and 1.95 g of (1E) -1- (tri-n-butylstannyl) -1-undecen- (3RS) -3-ol in 23 ml of dimethylformamide are present in the presence of 138 mg of 1,1'-bis (diphenylphosphino) ferrocene palladium-II chloride as a catalyst. The reaction mixture is poured onto ice and poured out with ethyl acetate shakes, the organic phase washed 4 times with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with hexane / ethyl acetate = 95/5. 161 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 2960, 2930, 2580, 1753, 1590, 1575, 1448, 1260 cm ^-1 .

EXAMPLE 12

2- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyloxy} acetic acid

Under the conditions of Example 2, 25 mg of methyl 2- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyloxy} in 1.5 ml of methanol are mixed with 1.5 ml of 1 n Saponified and processed sodium hydroxide solution. 20 mg of the title compound are obtained as a light yellow oil.

IR (CHCl ₃ ): 2960, 2930, 2857, 1735, 1588, 1574, 1448, 1260 cm ^-1 .

EXAMPLE 13

2- (3-methoxycarbonylbenzoyl) -6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine

Under the conditions of Example 1B, 652 mg of 2-bromo-6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine in 3 ml of tetrahydrofuran are mixed with 2.75 ml of n-butyllithium (1.6 molar in hexane) and 427 mg of dimethyl isophthalate in 3 ml of tetrahydrofuran, processed and chromatographed on silica gel with hexane / ethyl acetate = 95/5 to 75/25. 130 mg of crude oily product are obtained, which is subjected to complete purification of the high pressure liquid chromatography on silanized silica gel (RP 18 material) with methanol / H 0 = 85/15. 58 mg of the title compound are thus obtained as a colorless oil.

IR: 2928, 2858, 1728, 1668, 1580, 1440, 1272, 1235, 1162, 740, 725 cm ^-1 .

EXAMPLE 14

2- (3-carboxybenzoyl) - 6 - [(1 E) - (3 RS) - 3 - hydroxy-1-undecenyl l-pyridine

Under the conditions of Example 2, 20 mg of 2- (3-methoxycarbonyl- benzoyl) -6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine in 1 ml of methanol with 2 ml of 1N sodium hydroxide solution and prepared. 15 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 3018, 2963, 2930, 1720, 1670, 1607, 1265, 1100, 1015 cm ^-1 .

EXAMPLE 15

2- [3,5-bis (methoxycarbonyl) benzoyl] -6 - [(1E) - (3RS) -3-hydroxy-1-undecenylpyridine

Under the conditions of Example 1B, 1 g of 2-bromo-6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine in 10 ml of tetrahydrofuran is mixed with 4.26 ml of n-butyllithium (1.6 molar in hexane) and 807 mg of 1,3,5-benzenetricarboxylic acid trimethyl ester in 6 ml of tetrahydrofuran, processed and chromatographed on silica gel with hexane / ethyl acetate = 95/5 to 75/25. 203 mg of oily crude product are obtained, which is subjected to complete purification of the high pressure liquid chromatography on silanized silica gel (RP 18 material) using methanol / H ₂ O - 9/1. 74 mg of the title compound are thus obtained as a colorless oil.

IR (film): 3560-3160, 2920, 2850, 1730, 1670, 1590, 1450, 1345, 875, 850, 820 cm ^-1 .

EXAMPLE 16

2- [3,5-bis (carboxy) benzoyl] -6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine

Under the conditions of Example 2, 20 mg of 2- [3,5-bis (methoxycarbonyl) benzoyl] -6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine are added in 2 ml of methanol saponified with 2 ml of 1N sodium hydroxide solution and processed. 6 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 3580-3260, 3005, 1725, 1608, 1052, 1030, 1012, 930 cm ^-1 . EXAMPLE 17

(5RS) -5-Hydroxy-5- {6 - [(1E, 3E) - (5RS) -5-hydroxy-1,3-tridecadienyl] -2-pyridyl} pentanoic acid methyl ester

A. A solution of 5.88 g of 4-phosphonocrotonic acid triethyl ester in 60 ml of tetrahydrofuran is added in portions with 2.5 g of potassium tert-butoxide under stirring and under an argon atmosphere at -20 ° C. After 30 minutes, a solution of 2.6 g of 6-bromo-pyridine-2-aldehyde is added dropwise at -20 ° C. and the mixture is stirred at this temperature for a further hour. The reaction mixture is poured onto ice, shaken out with diethyl ether, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with hexane / ethyl acetate = 95/5. 2.66 g of ethyl 5- (6-bromo-2-pyridyl) - (E, E) -2,4-penta-dienoate are obtained as the crude product.

B. A solution of 2.6 g of 5- (6-bromo-2-pyridyl) - (E, E) -2,4-penta-dienoic acid ethyl ester in 73 ml of toluene is stirred and under an argon atmosphere at -70 ° C 15.4 ml of diisobutylaluminum hydride (20% solution in toluene) are added dropwise and the mixture is stirred at this temperature for a further 45 minutes. The reaction mixture is successively added dropwise at -70 ° C. with 5.5 ml of isopropanol and 7.3 ml of water, stirred for 1 hour at room temperature, suction filtered through diatomaceous earth, washed with dichloromethane, the filtrate dried over sodium sulfate and concentrated. 2.2 g of 5- (6-bromo-2-pyridyl) - (E, E) -2,4-pentadien-1-ol are obtained as a crude product.

C. A solution of 2 g of 5- (6-bromo-2-pyridyl) penta- (E, E) -2,4-dien-1-ol in 32 ml of dichloromethane is strengthened with 5.8 g of manganese dioxide for 2 hours touched. The reaction mixture is suction filtered through kieselguhr, concentrated and the residue is chromatographed on silica gel with dichloromethane. 1.17 g of 5- (6-bromo-2-pyridyl) - (E, E) -2,4-pentadienaldehyde are obtained as a crude product. D. A solution of 1.17 g of 5- (6-bromo-2-pyridyl) - (E, E) -2,4-penta-dienaldehyde in 25 ml of diethyl ether is stirred at -20 ° C. in a argon atmosphere Solution of octyl magnesium bromide (made from 150 mg magnesium in 5 ml diethyl ether and 1.14 g octyl bromide in 2.5 ml diethyl ether) was added dropwise. After 1.5 hours at -20 ° C, the reaction mixture is mixed with 15 ml of saturated ammonium chloride solution, extracted with diethyl ether, dried over sodium sulfate, concentrated and the residue is chromatographed on silica gel with hexane / ethyl acetate = 95/5. 477 mg of 2-bromo-6 - [(1E, 3E) - (5RS) -5-hydroxy-1,3-tridecadienyl] pyridine are obtained as a crude product.

E. Under the conditions of Example 1B, 470 mg of 2-bromo-6 - [(1E, - 3E) - (5RS) -5-hydroxy-1,3-tridecadienyl] pyridine in 7 ml of tetrahydrofuran are mixed with 1.84 ml n-butyllithium (1.6 molar in hexane) and 200 mg

5-Oxo-pentanoic acid methyl ester in 1.5 ml of tetrahydrofuran, treated, processed and chromatographed on silica gel with hexane / ethyl acetate = 95/5. 29 mg of the title compound are obtained as a colorless oil. IR (CHCl ₃ ): 3615, 2930, 1730, 1570, 1452, 1390, 1040, 875 cm ^-1 .

EXAMPLE 18

(5RS) -5-Hydroxy-5- {3 - [(1E, 3E) - (5RS) -5-hydroxy-1,3-tridecadienyl] phenyl} pentanoic acid

To a solution of 500 mg (5RS) -5-acetoxy-5- {3 - [(1E, 3E) - (5RS) -5-acetoxy-1,3-tridecadienyl] -phenyl} -pentan-1-ol- Tert-butyldimethylsilyl ether in 28 ml of tetrahydrofuran is added at 0 ° C with 914 mg of tetrabutylammonium fluoride, stirred for 30 minutes at 0 ° C and 4.5 hours at 24 ° C. The mixture is then diluted with ether, washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. With hexane / 0-20% ethyl acetate, 193 mg (5RS) - 5-acetoxy-5- {3 - {(1E, 3E) - (5RS) -5-acetoxy-1,3-tridecadieny} -phenyl} - are obtained. pentan-1-ol as a colorless oil.

IR (CHCl ₃ ): 3620, 3480, 2960, 2930, 2860, 1730, 1372, 1245, 1022, 990 cm ^-1 . A solution of 193 mg of the alcohol prepared above in 5 ml of methylene chloride is added dropwise to a mixture of 1.25 g of Collins reagent (chromic acid-pyridine complex) in 20 ml of methylene chloride at 0 ° C. while stirring, and the mixture is stirred at 0 ° for 1 hour C. Then enough Celite is added until a thick paste is formed, this is slurried with hexane / ethyl acetate (1: 1), filtered off, washed well with hexane / ethyl acetate (1: 1) and the filtrate is evaporated in vacuo. 150 mg of (5RS) -5-acetoxy-5- {3- [(1E, 3E) - (5RS) -5-acetoxy-1,3-tridecadienyl] phenyl} pentanal are obtained as a colorless oil.

IR (CHCl ₃ ); 3020, 2960, 2930, 2860, 2730, 1730, 1375, 1245, 1022, 990 cm ^-1 .

0.3 ml of Jones reagent (J. Chem. Soc. 1953, 2555) is added dropwise to a solution of 150 mg of the aldehyde prepared above in 11 ml of acetone with stirring at -30 ° C. and the mixture is stirred at -30 ° C. for one hour. Then 0.23 ml of isopropanol is added, the mixture is stirred for 15 minutes, diluted with ether, filtered, washed neutral with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. With

Hexane / 0-50% ethyl acetate gives 52 mg (5RS) -5-acetoxy-5- {3 - [(1E, 3E) - (5RS) -5-acetoxy-1,3-tridecadienyl] phenyl} pentane -acid as a colorless oil. IR (CHCl ₃ ): 3520, 3200, 2960, 2930, 2860, 1730, 1372, 1245, 1020, 990 cm ^-1 .

0.77 ml of 0.5N sodium hydroxide solution is added to a solution of 34 mg of the acid prepared above in 0.62 ml of methanol at 0 ° C. and the mixture is stirred at 24 ° C. for 1.8 hours. The mixture is then diluted with 2.5 ml of water and acidified to pH 6 with 0.5N sulfuric acid at 0 ° C. It is extracted three times with ethyl acetate, the organic phase is shaken with a little water, dried over sodium sulfate and evaporated in vacuo. The backlog is on

Chromatographed silica gel. With hexane / 30-85% ethyl acetate, 15 mg of the title compound is obtained as a colorless oil.

IR (film): 3420, 2960, 2930, 2860, 1723, 1380, 1070, 990 cm ^-1 . The starting material for the above title compound is prepared as follows:

A. 5- [3- (tert-Butyldimethylsilyloxymethyl) phenyl] - (2E, 4E) pentadienoic acid ethyl ester

33.3 g of tert are added at 0 ° C. under argon to a solution of 30 g of 3-hydroxymethylbenzyl alcohol and 30 g of imidazole in 250 ml of dimethylformamide. -Butyldimethylsilyl chloride and stirred for 20 hours at 25 ° C. It is diluted with 1.5 1 ether, shaken twice with 100 ml of 10% sulfuric acid, washed neutral with brine, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. With hexane / 0-80% ether, 23.4 g of 3-tert-butyldimethylsilyloxymethyl-benzyl alcohol are obtained as a colorless oil.

IR (CHCl ₃ ): 3680, 3610, 3440, 2960, 2930, 2860, 1470, 1255, 840 cm ^-1 .

A solution of 21 g of the silyl ether prepared above in 320 ml of methylene chloride is mixed with 82 g of manganese dioxide and stirred at 25 ° C. for 8 hours. It is then filtered and evaporated. 20.7 g of 3-tert-butyldimethylsilyloxymethylbenzaldehyde are obtained as a colorless oil.

IR (CHCl ₃ ): 2960, 2935, 2860, 1700, 1610, 1590, 1470, 125.5, 840 cm ^-1 .

For Wittig-Horner olefination, 14 g of potassium tert-butoxide are added at -20 ° C. to a solution of 33.4 g of triethyl phosphonocrotonic acid in 340 ml of tetrahydrofuran and the mixture is stirred at -20 ° C. for 30 minutes. A solution of 20 g of 3-tert-butyldimethylsilyloxymethylbenzaldehyde in 180 ml of tetrahydrofuran is then added dropwise to this solution and the mixture is stirred at -20 ° C. for 1 hour. It is then poured onto 700 ml of ice water, extracted three times with 500 ml of ether each time, the organic phase is washed neutral with brine, dried over sodium sulfate and evaporated in vacuo. The residue thus obtained is chromatographed on silica gel. With hexane / 0-30% ether, 25.8 g of the title compound is obtained as a colorless oil.

IR (CHCl ₃ ): 2960, 2935, 2860, 1705, 1627, 1470, 1370, 1245, 998, 840 cm ^-1 . B. 5- [3- (tert-Butyldimethylsilyloxymethyl) phenyl] - (2E, 4E) pentadienal

56 ml of an approximately 1.2 molar solution of diisobutylaluminum hydride in toluene are added dropwise to a solution of 10.6 g of the ester prepared according to Example 1A in 250 ml of toluene at -70 ° C. under argon and the mixture is stirred for one hour at -70 ° C. . 10 ml of isopropanol are then added dropwise, followed by 25 ml of water, and the mixture is stirred at 22 ° C. for 2 hours, filtered, washed with toluene and evaporated in vacuo. 10.6 g are obtained

5- [3- (tert-Butyldimethylsilyloxymethyl) phenyl] - (2E, 4E) -pentadien-1-ol as a colorless oil.

IR (CHCl ₃ ): 3610, 3450, 3005, 2960, 2935, 2860, 1470, 1380, 1255, 990, 840 cm ^-1 .

A solution of 10.6 g of the alcohol prepared above in 600 ml

38 g of brown stone are added to methylene chloride and the mixture is stirred at 25 ° C. for 4 hours. It is then filtered and evaporated. You get

7.8 g of the title compound as a colorless oil.

IR (CHCl ₃ ): 3605, 2960, 2935, 2860, 1675, 1622, 1470, 1245, 988, 840 cm ^-1 .

C. 5-Acetoxy-1- [3- (tert-butyldimethylsilyloxymethyl) phenyl] - (1E, 3E) - tridecadiene

A solution of 7.96 ml of n-octyl bromide in 12 ml of ether is added dropwise to 1.12 g of magnesium in 5 ml of ether, and the mixture is stirred at 25 ° C. for 30 minutes. 17 ml of this Grignard solution are added dropwise at -20.degree. Argon a solution of 7.8 g of the aldehyde prepared according to B in 150 ml of ether and stirred for 2 hours at -20 ° C. 100 ml of saturated ammonium chloride solution are added, the mixture is extracted three times with ether, the organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. 11 g of 5-hydroxy-1- [3- (tert-butyldimethylsilyloxymethyl) phenyl] - {1E, 3E) tridecadiene are obtained as a colorless oil. IR (CHCl ₃ ): 3610, 3460, 3000, 2960, 2930, 2860, 1470, 1255, 988, 840 cm ^-1 . For acetylation, 31 ml of acetic anhydride are added to a solution of 11 g of the alcohol prepared above in 120 ml of pyridine and the mixture is stirred for 15 hours at 23 ° C. The mixture is then concentrated in vacuo with the addition of toluene and the residue is chromatographed on silica gel. With hexane / 0-3% ethyl acetate, 8.9 g of the title compound is obtained as a colorless oil.

IR (CHCl ₃ ): 2960, 2937, 2860, 1730, 1470, 1372, 1255, 990, 840 cm ^-1 . (5RS) -5-acetoxy-5- {3 - [(1E, 3E) - (5RS) -5-acetoxy-1,3-tridecadienyl] phenyl} pentan-1-ol-tert-butyldimethylsilyl ether

4.9 g of tetrabutylammonium fluoride are added to a solution of 2.4 g of the acetate prepared according to C in 150 ml of tetrahydrofuran at 0 ° C. and the mixture is stirred at 24 ° C. for 1.5 hours. Then diluted with 250 ml of ether, shaken with brine, dried over sodium sulfate and evaporated in vacuo. The residue obtained is chromatographed on silica gel. With hexane / 0-25% ethyl acetate, 1.5 g of 3 - [(1E, 3E) 5-acetoxy-1,3-tridecadienyl] benzyl alcohol are obtained as a colorless oil.

IR (CHCl ₃ ): 3610, 3440, 3005, 2960, 2930. 2860, 1730, 1375, 1250, 990 cm ^-1 .

11 g of brown stone are added to a solution of 1.5 g of the benzyl alcohol prepared above in 30 ml of methylene chloride and the mixture is stirred at 24 ° C. for 3 hours. It is then filtered, washed with methylene chloride and evaporated in vacuo. 1.3 g of 3 - [(1E, 3E) -5-acetoxy-1,3-tridecadienyl] benzaldehyde are obtained as a colorless oil.

IR (CHCl ₃ ): 3020, 2960, 2930, 2860, 2740, 1727, 1695, 1600, 1372, 1245, 988 cm ^-1 .

A solution of 6.7 g of 4-chloro-1-tert-butyldimethylsilyloxybutane in 6 ml of tetrahydrofuran and 0.187 ml of dibromoethane is added dropwise to argon at 25 ° C. under argon at 25 ° C., heated to 70 ° C. for 5 minutes, stirred 30 Minutes at 25 ° C and diluted with 18.8 ml of tetrahydrofuran. A solution of 1.3 g of 3 - [(1E, 3E) -5-acetoxy-1,3-tridecadienyl] benzaldehyde in 16 ml of tetrahydrofuran is added dropwise to 16 ml of this organomagnesium solution at -70 ° C. under argon and stirred 1 , 5 hours at -70 ° C. 150 ml of saturated ammonium chloride solution are added, the mixture is extracted 3 times with ether, the organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is dissolved in 22 ml of pyridine, mixed with 12 ml of acetic anhydride and stirred at 22 ° C. for 16 hours. The mixture is then concentrated in vacuo with the addition of toluene and the residue is chromatographed on silica gel

(Flash chromatography). With hexane / 0-3.5% ethyl acetate, 1.1 g of the title compound is obtained as a colorless oil.

IR (CHCl ₃ ): 3005, 2960, 2930, 2860, 1730, 1372, 1250, 1095, 988, 838 cm ^-1 .

EXAMPLE 19

(5RS) -5-Hydroxy-5- {3- [{1E) - (3RS) -3-hydroxy-1-undecenyl] phenyl} pentanoic acid

To a solution of 630 mg (5RS) -5-acetoxy-5- {3 - [(1E) - (3RS) -3-diphenyl-tert-butylsilyloxy-1-undecenyl] phenyl} pentan-1-ol Tert-butyldimethylsilyl ether in 12 ml of ethanol is added at 22 ° C. under argon to 630 mg of pyridinium p-toluenesulfonate and stirred at 22 ° C. for 3.5 hours. Then diluted with ether, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. With hexane / 0-20% ethyl acetate, 472 mg (5RS) -5-acetoxy-5- {3- [(1E) - (3RS) -3-diphenyl-tert-butylsilyloxy-1-undecenyl] phenyl} are obtained. -pentan- 1-ol as a colorless oil.

IR (CHCl ₃ ): 3620, 3450, 3000, 2960, 2930, 2860, 1730, 1375, 1245, 1110, 965, 700 cm ^-1 .

4 g of Collins reagent (chromic acid-pyridine complex) are added at 0 ° C. under argon to a solution of 470 mg of the alcohol prepared above in 50 ml of methylene chloride and the mixture is stirred at 0 ° C. for 30 minutes. Then will add Celite until a thick paste is formed. This is slurried with hexane / ether (1 + 1), filtered off, washed well with hexane / ether (1 + 1) and the filtrate is evaporated in vacuo. 456 mg are obtained

(5RS) -5-Acetoxy-5- {3 - [(1E) - (3RS) -3-diphenyl-tert-butylsilyloxy-1-undecenyl] phenyl} pentanal as a colorless oil.

IR (CHCl ₃ ): 3000, 2960, 2930, 2860, 2730, 1728, 1372, 1245, 1110, 968,

700 cm ^-1 .

1 ml of Jones reagent (J. Chem. Soc. 1953, 2555) is added dropwise to a solution of 456 mg of the aldehyde prepared above in 20 ml of acetone with stirring at -30 ° C. and the mixture is stirred at -20 ° C. for 35 minutes. Then 0.3 ml of isopropanol is added, the mixture is stirred at -20 ° C. for 10 minutes, diluted with ether,

filtered, washed neutral with brine, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. With hexane / 0-50% ethyl acetate, 397 mg (5RS) -5-acetoxy-5- {3- [(1E) - (3RS) -3-diphenyl-tert-butylsilyloxy-1-undecenyl] phenyl} are obtained. -pentanoic acid as a colorless oil.

IR (CHCl ₃ ): 3520, 3180, 2950, 2930, 2860, 1730, 1375, 1245, 1110, 968,

700 cm ^-1 .

390 mg of tetrabutylammonium fluoride are added to a solution of 390 mg of the acid prepared above in 20 ml of tetrahydrofuran under argon at 24 ° C. and the mixture is stirred at 24 ° C. for 6 hours. The mixture is then diluted with ether, the organic phase is shaken with brine, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. With hexane / 10-70% ethyl acetate, 278 mg (5RS) -5-acetoxy-5- {3 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] phenyl} pentanoic acid are obtained as a colorless oil .

IR (CHCl ₃ ): 3610, 3520, 3200, 3010, 2960, 2930, 2860, 1730, 1375, 1245,

970 cm ^-1 .

0.5 N sodium hydroxide solution is added to a solution of 90 mg of the acid prepared above at 22 ° C. and the mixture is stirred for 2 hours at this temperature. Then it is diluted with 5 ml of water and at 0 ° C with 10%

Acidified sulfuric acid to pH 5. It is extracted four times with ethyl acetate shake the organic phase with brine, dry over sodium sulfate and evaporate in vacuo. The residue is chromatographed on silica gel. With hexane / 30-90% ethyl acetate, 61 mg of the title compound are obtained as a colorless oil.

IR (CHCl ₃ ): 3610, 3410, 3160; 3005, 2960, 2930, 2860, 1730, 1240, 968 cm ^-1 .

The starting material for the above title compound is prepared as follows:

A. 3-Diphenyl-tert-butylsilyloxy-1- [3- (tert-butyl-dimethylsilyloxymethyl) phenyl] - (1E) -undecene

For Wittig-Horner olefination, 3.64 g of potassium tert-butoxide are added at -20 ° C. to a solution of 9.41 g of dimethyl 2-0xo-decylphosphonate in 280 ml of tetrahydrofuran and the mixture is stirred for 20 minutes Temperature. A solution of 4.5 g of 3-tert-butyldimethylsilyloxymethylbenzaldehyde (see Example 18A) in 150 ml of tetrahydrofuran is then added dropwise to this solution and the mixture is stirred at -20 ° C. for one hour. It is poured onto 500 ml of saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase is washed neutral with brine, dried over sodium sulfate and evaporated in vacuo. The residue thus obtained is chromatographed on silica gel. With hexane / 5-20% ethyl acetate, 6.5 g of 1 - [3- (tert-butyldimethylsilyloxymethyl) phenyl] - (1E undecen- 3-one is obtained as a colorless oil.

IR (CHCl ₃ ): 3000. 2960, 2930, 1690, 1655, 1612, 1470, 1258, 970, 840 cm ^-1 .

483 mg of sodium borohydride are added to a solution of 6.5 g of the ketone prepared above in 270 ml of methanol under argon at 0 ° C. and the mixture is stirred for one hour at this temperature. 1.5 ml of glacial acetic acid are then added, the mixture is diluted with 150 ml of water and extracted three times with 200 ml of ethyl acetate each time. The organic phase is washed neutral with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. With hexane / 0-20% ethyl acetate, 5.65 g of 1- [3- (tert-butyldimethylsilyloxymethyl) phenyl] - (1E) -undecen-3-ol are obtained as a colorless oil.

IR (CHCl ₃ ): 3610, 3000, 2960, 2930, 2860, 1470, 1255, 968, 840 cm ^-1 .

3.6 g of imidazole and 6.18 g of tert-butyldiphenylsilyl chloride are added at 0 ° C. under argon to a solution of 5.65 g of the alcohol prepared above in 100 ml of dimethylformamide and the mixture is stirred at 22 ° C. for 16 hours. Then it is added to water, extracted with hexane / ether (1 + 1), the organic phase is washed with water and dried over

Sodium sulfate and evaporated in vacuo. The backlog is on Chromatographed silica gel. With hexane / 0-10% ethyl acetate you get

5.1 g of the title compound as a colorless oil.

IR (CHCl ₃ ): 3005, 2960, 2930, 2860, 1470, 1255, 970, 840, 700 cm ^-1 .

(5RS) -5- {3 - [(1E) - (3RS) -3-diphenyl-tert-butylsilyloxy-1-undecenyl] - phenyl} -5-acetoxy-pentan-1-ol-tert-butyldimethylsilyl ether

To a solution of the silyl ether prepared according to Example 19A in 100 ml of tetrahydrofuran is added 50 ml of a mixture of acetic acid / water / tetrahydrofuran (65 + 35 + 10), stirred for 8 hours at 50 ° C. and 16 hours at 24 ° C. The mixture is then evaporated with the addition of toluene and 5.1 g of 3 - [(1E) -3-diphenyl-tert-butylsilyloxy-1-undecenyl] benzyl alcohol are obtained as a colorless oil.

IR (CHCl ₃ ): 3610, 3470, 3000, 2960, 2930, 2860, 1470, 1250, 970 700 cm ^-1 .

6 g of brown stone are added to a solution of 1.5 g of the alcohol prepared above in 20 ml of methylene chloride and the mixture is stirred at 22 ° C. for 4 hours. Then it is filtered through Celite, washed with methylene chloride and evaporated in vacuo. The residue is chromatographed on silica gel. With hexane / ethyl acetate (9 + 1), 1.47 g of 3- [(1E) -3-diphenyl-tert-butylsilyloxy-1-undecenyl] benzaldehyde are obtained as a colorless oil.

IR (CHCl ₃ ): 3000, 2960, 2930, 2860, 2740, 1700, 1605, 1112, 970, 705 cm ^-1 .

20 ml of a Grignard solution of 4-chloro-1-tert-butyldimethylsilyloxybutane and magnesium in tetrahydrofuran (see example) are added dropwise under argon at -70 ° C. to a solution of 1.47 g of the aldehyde prepared above in 10 ml of tetrahydrofuran 18D) and stir for 30 minutes. It is added to saturated ammonium chloride solution, extracted with ether, the organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in 8 ml of pyridine, 2 ml of acetic anhydride are added and the mixture is stirred at 24 ° C. for 20 hours. The mixture is then concentrated in vacuo with the addition of toluene and chromatograph the residue on silica gel. With hexane / 0-15% ethyl acetate, 630 mg of the title compound is obtained as a colorless oil.

IR (CHCl ₃ ): 3000, 2965, 2940, 2855, 1730, 1470, 1375, 1250, 1105, 968,

840, 700 cm ^-1 .

EXAMPLE 20

5- {6- [1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyl} -4-oxo-pentanoic acid, methyl ester

A. A solution of 4.73 g of 2,6-dibromopyridine in 150 ml of triethylamine is treated with 2.69 g of methyl pentynate, 350 mg of bis-triphenylphosphine-palladium-II-chloride and 48 mg of copper-I-iodide while cooling with ice and the mixture is 1 Hour stirred. The ice bath is then removed and the mixture is stirred at room temperature for 3 hours. The precipitate - consisting of 2,6-bis- (4-methoxycarbonyl-1-butynyl) pyridine and triethylammonium bromide - is filtered off and the filtrate is evaporated to dryness. The residue is chromatographed on silica gel with hexane / ethyl acetate = 95/5 to 75/25. 2.32 g of methyl 5- (6-bromo-2-pyridyl) -4-pentynate with a melting point of 59-61 ° C. are obtained.

IR (KBr): 3040, 2230, 1728, 1572, 1548, 1433, 1162, 800 cm ^-1 .

B. A mixture of 500 mg of red mercury oxide, 0.2 ml of boron trifluoride-diethyl ether complex and 10 mg of trichloroacetic acid in 1 ml of methanol is heated to 60 ° and a solution of 9.4 g of 5- (6- Bromo-2-pyridyl) -4-pentynate in 15 ml of methanol and the mixture was stirred for 2 hours at room temperature. Then the reaction mixture in 5%

Poured sulfuric acid, extracted with ethyl acetate, dried

(Na ₂ SO ₄ ) and concentrated. 6.3 g of methyl 5- (6-bromo-2-pyridyl) -4-oxopentanoate are obtained as a light yellow oil.

IR: 2955, 1738, 1720, 1585, 1555, 1440, 1410, 1360, 1200, 1165, 1120, 988 cm ^-1 .

C. Under the conditions of Example 5B, 1.3 g of methyl 5- (6-bromo-2-pyridyl) -4-oxo-pentanoate and 2.31 g of (1E) -1-tri-n-butylstannyl) - 1-undecen- (3RS) -3-ol in 13 ml dimethylformamide in the presence of 320 mg 1,1'-bis (diphenylphosphino) ferrocene palladium-II-chloride implemented as a catalyst, and processed analogously to Example 11B. The crude product is chromatographed on silica gel with hexane / ethyl acetate 95/5 to 75/25. 300 mg of the title compound are obtained as a light yellow oil.

IR (CHCl ₃ ): 3610, 2925, 1738, 1725, 1573. 1453, 1260, 1040 cm ^-1 .

EXAMPLE 21

(4RS) -4-Hydroxy-5- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridyl} pentanoic acid

A. 72 mg of sodium borohydride are added to a solution of 490 mg of methyl 5- (6-bromo-2-pyridyl) -4-oxopentanoate in 20 ml of methanol, with ice cooling, and the mixture is stirred at 0-3 ° C. for 1 hour. Then 2 ml of acetone are added, the mixture is stirred for 1 hour and the reaction mixture is evaporated to dryness. The residue is partitioned between water and ethyl acetate, the organic phase is dried over sodium sulfate and concentrated. 421 mg of 5 - [(6-bromo-2-pyridyl) methyl] tetrahydrofuran-2-one are obtained as a yellow oil.

IR (CHCl ₃ ): 1765, 1583, 1553, 1423, 1170, 1160, 1118, 1020, 985 cm ^-1 .

B. Under the conditions of Example 11 B, 400 mg of 5 - [(6-bromo-2-pyridyl) methyl] tetrahydrofuran-2-one and 780 mg of (1E) -1- (tri-n-butyl-stannyl ) -1-undecen- (3RS) -3-ol in 5 ml of dimethylformamide in the presence of 112 mg of 1,1'-bis (diphenylphosphino) ferrocene-palladium-II-chloride as a catalyst and processed. The crude product is chromatographed on silica gel with hexane / 0-30% ethyl acetate. 146 mg of 5- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyl-methyl} - tetrahydrofuran-2-one are obtained as a yellow oil.

IR (CHCl ₃ ): 2915, 2840, 1762, 1667, 1585, 1570, 1450, 1350, 1170, 970 cm ^-1 . C. Under the conditions of Example 2, 30 mg of 5- {6 - [(1E) - (3RS) - 3-hydroxy-1-undecenyl] -2-pyridyl-methyl} -tetrahydrofuran-2-one in 2 ml of methanol saponified and prepared with 1 ml of 1N sodium hydroxide solution.

20 mg of the title compound are obtained as an oil.

IR (CHCl ₃ ): 3550-3080, 2920, 1724, 1585, 1570, 1450, 1255, 1090, cm ^-1 .

EXAMPLE 22

5- [6- (1E) - (3RS) -3-Hydroxy-1-undecenyl] -2-pyridyl} - (4RS) -4-hydroxypentan- 1-ol

A. A solution of 500 mg of 5 - [(6-bromo-2-pyridyl) methyl] tetrahydrofuran 2-one in 13 ml of triethylamine and 2 ml of tetrahydrofuran is mixed with 350 mg (3RS) -1-undecin-3- ol, 37 mg of bis- (triphenylphosphine) palladium-II-chloride and 5 mg of copper-I-iodide are added and the mixture is stirred for 3 days at room temperature. The reaction mixture is evaporated to dryness, partitioned between water and ethyl acetate, dried over sodium sulfate, concentrated and the residue is chromatographed on silica gel with hexane / 0-35% ethyl acetate. 294 mg of 5- {6 - [(3RS) -3-hydroxy-1-undecinyl] -2-pyridyl-methyl} -tetrahydrofuran-2-one are obtained as an oil.

IR (CHCl ₃ ): 2920, 2850, 2220, 1768, 1585, 1450, 1173 cm ^-1 .

The representation of (3RS) -1-undecin-3-ol is described in German patent application P 39 09 326.3.

B. To a solution of 0.725 ml of sodium bis (2-methoxyethoxy) aluminum hydride (3.5 molar in toluene), which was diluted with 3.75 ml of toluene, a solution of is in an argon atmosphere at 0 ° C. 145 mg 5- {6-

[(3RS) -3-Hydroxy-1-undecinyl] -2-pyridyl-methyl} -tetrahydrofuran-2-one was added dropwise in 1.2 ml of toluene. When the addition is complete, the reaction mixture is stirred at room temperature and 0.5 ml of isopropanol and 0.5 ml of water are added in succession after 3 hours with ice cooling. The precipitate is filtered off with suction, washed with ethyl acetate, the filtrate is concentrated and the residue is chromatographed on silica gel with methylene chloride / 0-5% methanol. 22 mg of the title compound are obtained as a yellow oil.

IR (CHCl ₃ ): 3550-3080, 2920, 2859, 1585, 1570, 1450, 1255, 1180 cm ^-1 .

EXAMPLE 23

(5RS) -5-Hydroxy-5- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyl} - ppntan-1-ol

A. A solution of 4 g of 2-bromo-6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine in 20 ml of dimethylformamide is mixed with 4.1 g of tert-butyl-diphenylsilyl chloride and 2 , 1 g imidazole and stirred for 15 hours at room temperature. The reaction mixture is poured into 100 ml of diethyl ether, shaken twice with 20 ml of 1N hydrochloric acid, 4 times with 20 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with hexane / 0-5% ethyl acetate. 5.5 g of 2-bromo-6 - [(1E) - (3RS) -3-tert-butyldiphenylsilyloxy-1-undecenyl] pyridine are obtained as an oil.

IR (CHCl ₃ ): 2925, 2850, 1578, 1548, 1426, 1110, 983, 820, 695 cm ^-1 .

B. To a suspension of 500 mg of 2-bromo-6 - [(1E) - (3RS) -3-tert-butyl-diphensilyloxy-1-undecenyl] pyridine in 2 ml of diethyl ether and 1 ml

Tetrahydrofuran are added dropwise at -80 ° under an argon atmosphere to 1.16 ml of n-butyllithium (1.6 molar in hexane). After the addition has ended, the reaction mixture is stirred at -40 ° C. for 15 minutes, cooled to -80 ° C. and 140 mg of dimethylformamide are added dropwise at this temperature. After 4 hours at -80 ° C., the reaction mixture is hydrolyzed with 3 ml of 2N hydrochloric acid, the organic phase is separated off, dried over sodium sulfate and concentrated, and the residue on silica gel with hexane / 0-10%. Chromatographed ethyl acetate. There will be 385 mg

6 - [(1E) - (3RS) -3-tert-butyl-diphenyisilyloxy-1-undecenyl] pyridine-2-carbaldehyde was obtained as a yellow oil.

IR (CHCl ₃ ): 2915, 2845, 1705, 1768, 1580, 1450, 1420, 1105, 695 cm ^-1 . C. 5.1 ml of a Grignard solution (prepared from 385 mg of magnesium and 1.76 g of 4-chloro-1-tert-butyldimethylsilyloxybutane in tetrahydrofuran) are converted into a solution of 370 mg at -80 ° C 6 - [(1E) - ( 3RS) -3-tert.-

Butyl-diphenylsilyloxy-1-undecenyl] pyridine-2-carbaldehyde was added dropwise in 3 ml of tetrahydrofuran. After stirring for 2 hours at -80 ° C, the reaction mixture is poured into 10 ml of saturated ammonium chloride solution, shaken with ethyl acetate, the organic phase is dried and concentrated. The residue is dissolved in 10 ml of tetrahydrofuran, mixed with 2.47 g of tetrabutylammonium fluoride and at 17 hours.

Room temperature door - stirred. The reaction mixture is poured into 50 ml of diethyl ether, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is on silica gel with hexane / 0-30%. Chromatographed ethyl acetate. 110 mg of the title compound are obtained as yellow 01.

IR (CHCl ₃ ): 2920, 2850, 1590, 1570, 1455, 1258, 1075, 1015, 970 cm ^-1 .

EXAMPLE 24

2 - [(2RS) -2-Hydroxy-2- (3-methoxycarbonylphenyl) ethyl] -6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine

A. A solution of 15.1 g of 2,6-dibromopyridine in 500 ml of triethylamine is cooled with 10.2 g of methyl 3-ethynylbenzoate, 1.1 g of bis- (triphenylphosphine) palladium-II-chloride and 150 mg of copper with ice cooling. I-iodide was added and the mixture was stirred for 1 hour. The ice bath is then removed and the mixture is stirred at room temperature for 48 hours. The precipitate is filtered off, the filtrate is evaporated to dryness, water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and the residue is chromatographed on silica gel with hexane / 0-12% ethyl acetate. 4.8 g of 2-bromo-6- [2- (3-methoxycarbonylphenyl) ethynyl] pyridine of melting point 124-126 ° C. are obtained.

IR (CHCl ₃ ): 2980, 2210, 1715, 1570, 1430, 1280, 1260, 1165, 1103 cm ^-1 . B. A solution of 5.2 g of 2-bromo-6- [2- (3-methoxycarbonylphenyl) ethynyl] pyridine in 30 ml of 60% sulfuric acid is heated to 140 ° C. for 1.5 hours with stirring. After cooling to room temperature, the reaction mixture is poured onto ice water, the precipitate is suction filtered and washed neutral with water. After drying at 50 ° C. in vacuo, the crude product is dissolved in 35 ml of methanol, 3 drops of concentrated sulfuric acid are added and the mixture is heated under reflux for 8 hours. The reaction mixture is then concentrated, partitioned between water and ethyl acetate, the organic phase washed with 10% sodium hydrogen carbonate and water, dried over sodium sulfate and concentrated. 3.5 g of 2-bromo-6 - [(3-methoxycarbonylbenzoyl) methyl] pyridine of melting point 84-86 ° C. are obtained.

IR (CHCl ₃ ): 1720, 1633, 1590, 1438. 1300, 1165 cm ^-1 .

C. A solution of 2.4 g of 2-bromo-6- [2- (3-methoxycarbonylbenzoyl) methyl] pyridine in 100 ml of methanol is mixed with 293 mg of sodium borohydride while cooling with ice, at 0 ° C. for 1 hour and stirred overnight at room temperature. Then 3 ml of acetone are added, stirring is continued for half an hour and the reaction mixture is evaporated to dryness. The residue is partitioned between water and ethyl acetate, the organic phase is dried with sodium sulfate and concentrated. There are 2.33 g

2-Bromo-6 - [(2RS) -2-hydroxy-2- (3-methoxycarbonylphenyl) ethyl] pyridine obtained as a yellow oil.

IR (CHCl ₃ ): 3540-3280, 1715, 1585, 1550, 1434, 1285, 1104 cm ^-1 . D. A solution of 120 mg of 2-bromo-6 - [(2RS) -2-hydroxy-2- (3-ethoxycarbonylphenyl) ethyl] pyridine in 0.7 ml of toluene is mixed with 180 mg (1E) - 1- (Tri- n-butylstannyl) -1-undecen- (3RS) -3-ol and 22 mg 1,1'-bis- (diphenyl-phosphino) -ferrocene-palladium-II-chloride are added and the mixture is stirred for 2 hours under an argon atmosphere stirred at 100 ° C. The reaction mixture is evaporated to dryness and the residue is chromatographed on silica gel with hexane / 0-15% ethyl acetate. 56 mg of the title compound are obtained as an oil.

IR (CHCl ₃ ): 2920, 2850, 1715, 1500, 1450, 1285, 1260 1090, 1005 cm ^-1 . EXAMPLE 25

2 - [(2RS) -2-Hydroxy-2- (3-carboxyphenyl) ethyl] -6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine

Under the conditions of Example 2, 30 mg of 2 - [(2RS) -2-hydroxy-2- (3-methoxycarbonylphenyl) ethyl] -6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] - Saponified and prepared pyridine in 2 ml of methanol with 1 ml of 1N sodium hydroxide solution. 18 mg of the title compound are obtained as an oil.

¹ H-NMR (300 MHz. CD ₂ Cl ₂ , δ ppm): 0.80 (t, J = 6Hz, 3H): 1.0-1.62 (14H);

2.95-3.17 (2H); 4.21-4.32 (1H); 5.08-5.20 (1H); 6.57-6.72 (2H);

6.90-6.98 (1H); 7.11 - 7.20 (1H); 7.32 - 7.42 (1H); 7.50-7.65 (2H);

7.82-7.93 (1H); 8.02-8.13 (1H).

EXAMPLE 26

2 - [(2RS) -2-Hydroxy-2- (3-hydroxymethylphenyl) ethyl] -6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] pyridine

A. A solution of 180 mg of 2-bromo-6 - [(2RS) -2-hydroxy-2- (3-methoxycarbonylphenyl) ethyl] pyridine in 4 ml of toluene is dissolved in an argon atmosphere at -70 ° C with 0 , 88 ml of diisobutylaluminum hydride (20% in toluene) were added and the mixture was stirred at this temperature for 3 hours. The reaction mixture is successively mixed at -70 ° C with 0.3 ml of isopropanol and 0.3 ml of water and stirred overnight at room temperature. The precipitate is filtered off, the filtrate is dried over sodium sulfate and concentrated. The crude product is dissolved in 3 ml of methanol, mixed with 82 mg of sodium borohydride and stirred overnight at room temperature. The reaction mixture is acidified to pH 1 with 2N hydrochloric acid, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated, and the residue on silica gel with hexane / 0-10%. Chromatographed ethyl acetate. 103 mg of 2-bromo6 - [(2RS) -2-hydroxy-2- (3-hydroxymethylphenyl) ethyl] pyridine are obtained as a colorless oil.

IR (CHCl ₃ ): 3680-3080, 2910, 2860, 1580, 1548, 1430, 1400, 1150, 1113, 1040, 788 cm ^-1 . B. Under the conditions of Example 24D, 96 mg of 2-bromo-6-

[(2RS) -2-Hydroxy-2- (3-hydroxymethylphenyl) ethyl] pyridine and 160 mg (1E) -1- (Tri-n-butyl-stannyl) -1-undecen- (3RS) -3- ol in 1 ml of toluene in the presence of 1,1'-bis- (diphenylphosphino) -ferrocene-palladium-II-chloride as a catalyst and processed. The crude product is chromatographed on silica gel with hexane / 0-25% ethyl acetate. 20 mg of the title compound are obtained as a wine-red oil.

IR (CHCl ₃ ): 2920, 2845, 1584, 1567, 1448, 1253, 1090, 1007 cm ^-1 .

EXAMPLE 27

5- {6 - [(1E) - (3RS) -3-Hydroxy-1-undecenyl] -2-pyridyl} -4-pentic acid

A. Under the conditions of Example 11 B, 1.4 g of methyl 5- (6-bromo-2-pyridyl) -4-pentate and 5.75 g of (1E) -1- (tri-n-butylstannyl) - 1-undecen- (3RS) -3-ol in 30 ml of dimethylformamide in the presence of 185 mg of 1,1'-bis (diphenylphosphino) ferrocene-palladium-II-chloride as a catalyst and processed. The crude product is chromatographed on silica gel with hexane / 0-20% ethyl acetate. 354 mg of methyl 5- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyl} -4-pentynate are obtained as a yellow oil.

IR (CHCl ₃ ): 3030, 2400, 1740, 1520, 1430, 1218, 1048, 930 cm ^-1 .

B. Under the conditions of Example 2, 20 mg of 5- {6 - [(1E) - (3RS) - 3-hydroxy-1-undecenyl] -2-pyridyl} -4-pentynoic acid methyl ester in 1 ml of methanol are mixed with 2 ml of 1 n Saponified and processed sodium hydroxide solution. 11 mg of the title compound are obtained as a yellow oil.

IR (CHCl ₃ ): 3690, 3040, 3020, 2930, 2860, 2400, 1730, 1605, 1260, 1100, 1015, 930 cm ^-1 .

Claims

PATENT CLAIMS

1. Leukotriene B ₄ analogs of the formula I,

wherein

R ^{1 represents} the radical COOR ² with R ² meaning a hydrogen atom or a (C ₄ -C ₄ ) alkyl group or R ^{1 represents} the radical CH ₂ OH,

B is an alkylene group with 1-3 carbon atoms in the chain, a residue

in the meaning of a

Hydrogen atom, a carboxy or methoxycarbonyl group,

A the groups -O-, -NH-CO-, -CO-NH-, -OCH ₂ - -CH = CH-, -C≡C-,

-COCH ₂ -,

or -CHOH-CH ₂ -,

X N or CH,

D the groups or and

2. Process for the preparation of leukotriene B ₄ analogs of the formula I,

wherein

R ^{1 represents} the radical COOR ² with R ² meaning a hydrogen atom or a (C ₁ -C ₄ ) alkyl group or R ^{1 represents} the radical CH ₂ OH,

B is an alkylene group with 1-3 carbon atoms in the chain, a residue

with R ³ in the meaning of a

Hydrogen atom, a carboxy or methoxycarbonyl group,

A the groups -O-,, -NH-CO-, -CO-NH-, -OCH ₂ -, -CH = CH-, -C≡C-,

or -CHOH-CH ₂ -,

X N or CH,

D the groups or and

..... mean a single or double bond, and optionally their salts with physiologically acceptable bases, characterized in that one in a conventional manner

a) a compound of formula II

in which D has the meaning given above and .... represents a single or a double bond and X represent nitrogen and in which Z symbolizes a bromine atom or an iodine atom, after reaction with n-butyllithium with a compound of the formula III R ¹ -BR ⁴ ( III), wherein R ¹ and B have the meanings given above and R ⁴ the radicals

-CHO or -COOCH ₃ means, converts, or

b) a compound of the formula IV,

(IV),

in which R ¹ , B, A and Z have the meanings given above and X is nitrogen, with a tri-n-butylstannane of the formula V,

wherein ..... represents a single or a double bond, in the presence of a palladium catalyst, or

c) a phenyl derivative of the formula VI,

where D is the groups or Ac is an acyl group with bi s

to 8 carbon atoms and ... mean a single or a double bond, with a Grignard compound of the general formula VII

wherein B has the meaning given above, Y is a chlorine atom or a

Represents bromine atom and the substituents R ₅ , R ₆ and R _{7 are} identical or different and mean C ₁ -C ₄ alkyl groups or phenyl groups, the free hydroxyl group acylates the silyl ether and, if desired, the

Hydroxymethyl compound oxidized to the carboxyl compound, as well as existing ones

The acyl groups are split off and the carboxyl group is esterified or converted into its salts.